While enormous effort has gone into understanding the molecular events in acquired resistance, not much attention has been given to what happens during treatment, particularly during the early phase when patients still respond to drug treatment. Venetoclax (ABT-199), a novel potent and selective small-molecule BCL-2 inhibitor, has recently emerged as an effective therapy for hematopoietic tumors including MCL. While responses to ABT-199 can often be dramatic, they are rarely durable, and there is a significant need to improve the duration of response and delay or prevent drug resistance (DR). We modeled drug resistance to ABT-199 by generating ABT-199 resistant cell lines from MCL, and characterized the adaptive molecular reprogramming to ABT-199 treatment in MCL lines and primary samples. More complex and more dynamic than we had anticipated, we consistently detected a small subpopulations of lymphoma cells that evade strong selective ABT-199 pressure by entering a reversible drug tolerant 'persister' state (DTP), leading to DTP expansion population (DTEP) and eventual acquisition of bona fide drug resistance. We observed that these DTEP cells are conferred increased survival, clonogenic growth and are associated with BH3 family protein reprogramming. Intriguingly, DTEP cells revert back to drug sensitive states after long term passage without the drug, supporting that these cells are epigenetically reprogrammed to drug resistant states. Consistent with these results, by using drug screen approaches, we observed that epigenetic regulators such as BRD4, PRMT5, CDK9 and EP300 are required for and contribute to drug tolerance and drug resistance evolution. Most recently, RNA sequencing (RNA-seq) and ChIP-seq against H3K27Acrevealed super-enhancers (SE) remodeling in DTEP cells, supporting that epigenetically regulated SEs remodeling is required for transcriptional reprogramming and drug resistance evolution. Our central hypothesis is that transcriptional and epigenetic adaptive response and coordination in response to ABT-199 treatment confer MCL drug tolerance and therapeutic vulnerability to prevent subsequent drug resistance evolution in MCL. The objective of this proposal is to strategically target epigenetic transcription machinery and provide pre-clinical validation of combination of epigenetically targeting with BCL-2 antagonist as a therapeutic approach against MCL. The study allows us to gain valuable insights into MCL drug resistance biology and uncover a novel mechanism- driven therapy for MCL patients.